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Sci Transl Med. 2019 Dec 18;11(523). pii: eaav5264. doi: 10.1126/scitranslmed.aav5264.

Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology.

Author information

1
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
2
Project MinE ALS Sequencing Consortium.
3
Department of Neurosciences, UC San Diego, La Jolla, CA 92093, USA.
4
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
5
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
6
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
7
Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel.
8
Stem Cell Core and Advanced Cell Technologies Unit, Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel.
9
Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
10
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
11
Integrated DNA Technologies, 1710 Commercial Park, Coralville, IA 52241, USA.
12
Department of Neurology, School of Medicine, University of Washington, Seattle, WA 98195, USA.
13
Department of Neurology, Inselspital University Hospital, University of Bern, Freiburgstrasse 16, CH-3010 Bern, Bern, Switzerland.
14
Department for BioMedical Research, University of Bern, Murtenstrasse 40, CH-3008 Bern, Switzerland.
15
Department of Neurology, Columbia University, New York, NY 10032, USA.
16
Gene Expression Laboratory and the Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
17
Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands.
18
Center for Genomics of Neurodegenerative Disease (CGND) and New York Genome Center (NYGC) ALS Consortium, New York, NY 10013, USA.
19
Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, Department of Basic and Clinical Neuroscience, Department of Neurology, King's College London, London SE5 9RX, UK.
20
Department of Neurology, King's College Hospital, London SE5 9RS, UK.
21
Koç University Translational Medicine Research Center, NDAL, Istanbul 34010, Turkey.
22
Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin 2, Republic of Ireland.
23
Department of Neurology, Beaumont Hospital, Dublin 2, Republic of Ireland.
24
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
25
ALS Unit, Hospital San Rafael, Madrid 28016, Spain.
26
Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
27
Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK.
28
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
29
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel. eran.hornstein@weizmann.ac.il.

Abstract

Motor neuron-specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.

PMID:
31852800
DOI:
10.1126/scitranslmed.aav5264
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